Extracorporeal CO2 Elimination (ECCO2R) for Hypercapnic Respiratory Failure: From Pathophysiology to Clinical Application

Introduction: Hypercapnic respiratory failure is associated with high morbidity and mortality. Low-flow extracorporeal CO2 removal (ECCO2R) has been shown to facilitate lung-protective ventilation or spontaneous breathing. However, three multicenter randomized trials have failed to show benefit which could potentially be a result of patient selection. In this study, we aimed to characterize prognostic scores developed for extracorporeal membrane oxygenation therapy which could potentially assist with the selection of patients for ECCO2R. Methods: A total of 70 patients admitted to the intensive care unit at the University Hospital of Zurich between 10/2009 and 02/2017 with hypercapnic respiratory failure were treated with ECCO2R if pH ≤7.25 and/or PaCO2 ≥ 9 kPa experiencing respiratory exhaustion during spontaneous breathing in obstructive lung disease or reaching the limits of lung protective ventilation (n = 22 and n = 48) in patients with restrictive lung pathologies. Data including baseline characteristics and respiratory parameters were collected prospectively. Scores were calculated retrospectively. Results: The underlying diseases were acute respiratory distress syndrome (n = 27), chronic-obstructive pulmonary disease (n = 12), bronchiolitis obliterans syndrome (BOS; n = 9), cystic fibrosis (n = 10), pulmonary fibrosis (n = 8), and other causes (n = 4). The 180-day mortality was 45.7% with the highest rate observed in PF and BOS patients as well as in patients who had been mechanically ventilated >6 days before initiation of ECCO2R. The modified PRedicting dEath for SEvere hypercapnic respiratory failure on vv-ECCO2R (PRESERVE-CO2) score differentiated well between survivors and non-survivors (4.3 ± 2.2 vs. 6.9 ± 2.6, p < 0.01), whereas the modified Respiratory ECMO Survival Prediction (RESP-CO2) score showed no significant distinction. Receiver operating characteristics analysis of the PRESERVE-CO2 score revealed an area under the curve of 0.78, suggesting a cut-off of 7 points. Conclusion: Careful selection of patients for ECCO2R therapy may help to improve outcomes. The proposed PRESERVE-CO2 score may serve as a guide. A score of 7 points or higher is associated with an unfavorable outcome regarding the 180-day mortality in the specific patient cohort of this study, but future studies to externally validate this score are required.

In patients with acute respiratory failure, severe respiratory acidosis is managed by either invasive or noninvasive ventilation (NIV).&#13;\nRecent data suggest that mechanical ventilation may be supported by extracorporeal CO2 removal (ECCO2R) to manage the severe&#13;\nrespiratory acidosis consequent to super protective ventilatory strategies in patients with acute respiratory distress syndrome or failure of NIV in patients with acute hypercapnic respiratory failure.This pilot physiological report demonstrates that in patients with chronic obstructive pulmonary disease who are not yet ready to be weaned, the addition of ECCO2R during unsupported breathing avoids the increase in PaCO2 and inspiratory effort and the occurrence of a rapid shallow breathing pattern.We hope these results encourage future investigations on the use ECCO2R to facilitate the weaning process.

BackgroundInvasive mechanical ventilation is lifesaving in the setting of severe acute respiratory failure but can cause ventilation-induced lung injury. Advances in extracorporeal CO2 removal (ECCO2R) technologies may facilitate more protective lung ventilation in acute respiratory distress syndrome, and enable earlier weaning and/or avoid invasive mechanical ventilation entirely in chronic obstructive pulmonary disease exacerbations. We evaluated the in vitro CO2 removal capacity of the novel PrismaLung+ ECCO2R device compared with two existing gas exchangers.MethodsThe in vitro CO2 removal capacity of the PrismaLung+ (surface area 0.8 m2, Baxter) was compared with the PrismaLung (surface area 0.35 m2, Baxter) and A.L.ONE (surface area 1.35 m2, Eurosets) devices, using a closed-loop bovine blood–perfused extracorporeal circuit. The efficacy of each device was measured at varying pCO2 inlet (pinCO2) levels (45, 60, and 80 mmHg) and blood flow rates (QB) of 200–450 mL/min; the PrismaLung+ and A.L.ONE devices were also tested at a QB of 600 mL/min. The amount of CO2 removed by each device was assessed by measurement of the CO2 infused to maintain circuit equilibrium (CO2 infusion method) and compared with measured CO2 concentrations in the inlet and outlet of the CO2 removal device (blood gas analysis method).ResultsThe PrismaLung+ device performed similarly to the A.L.ONE device, with both devices demonstrating CO2 removal rates ~ 50% greater than the PrismaLung device. CO2 removal rates were 73 ± 4.0, 44 ± 2.5, and 72 ± 1.9 mL/min, for PrismaLung+, PrismaLung, and A.L.ONE, respectively, at QB 300 mL/min and pinCO2 45 mmHg. A Bland–Altman plot demonstrated that the CO2 infusion method was comparable to the blood gas analysis method for calculating CO2 removal. The resistance to blood flow across the test device, as measured by pressure drop, varied as a function of blood flow rate, and was greatest for PrismaLung and lowest for the A.L.ONE device.ConclusionsThe newly developed PrismaLung+ performed more effectively than PrismaLung, with performance of CO2 removal comparable to A.L.ONE at the flow rates tested, despite the smaller membrane surface area of PrismaLung+ versus A.L.ONE. Clinical testing of PrismaLung+ is warranted to further characterize its performance.

Objective: Noninvasive ventilation (NIV) had been successfully used in patients with severe hypercapnic acute respiratory failure (HARF). Being lack of a large number of randomized control trials to support NIV in chronic obstructive pulmonary disease (COPD) patients with severe HARF, the effect of NIV for patients with life-threatening HARF should be further confirmed. In order to confirm the effect of NIV on selected patients with HARF due to COPD, we conducted a comparative prospective observational study of NIV vs. IMV (invasive mechanical ventilation) + NIV in COPD patients with HARF. Methods: A total of 420 patients with acute respiratory failure secondary to COPD were prospective screened; 52 cases with PaCO2 ≥ 90 mmHg or PaCO2 <90 mmHg but ≥ 80 mmHg with pH value ≤ 7.20 were enrolled. Twentyone cases received sequential IMV to NIV treatment and were designated as the IMV+NIV group; 31 cases received NIV and were designated as the NIV group. The primary outcome was hospital mortality and mortality within 30 days of discharge. The secondary outcomes included risk factors for mortality and re-hospitalization, length of hospital stay, time of mechanical ventilation and re-admission rate within 30 days of discharge. Results: Mortality in-hospital and within 30 days of discharge had no differences between NIV group and IMV +NIV group (p=0.699). Binary logistic regression found no risk factor for mortality and re-hospitalization in two groups. The length of hospital stay (p=0.000) and time of mechanical ventilation (p=0.000) were significantly longer in the IMV+NIV group compared with the NIV group. Conclusion: Compared to IMV+NIV, NIV has similar efficacy for select patients with severe HARF secondary to acute exacerbation of COPD, and NIV can be safely used in these patients.

Introduction. Extracorporeal membrane oxygenation (ECMO) support for severe acute respiratory distress syndrome (ARDS) is nowadays widely used with notable results on the overall survival as reported in the ELSO registry near to 55% at 90 days. This is the reason why ECMO teams force the use of this extreme technique to several populations, even though there is still a lack of data about its use on hematological patients. Case Report. A 39-year-old woman without a history of previous diseases, but a new diagnosis of acute myeloblastic leukemia (AML) was admitted to intensive care unit (ICU) for worsening hypoxia and respiratory acidosis, presenting an ARDS with PaO2/FiO2 < 100 in spontaneous breathing treated with noninvasive ventilation via full-face mask. Meanwhile, chemotherapy was started leading to a severe bone marrow aplasia that was managed with multiple blood and platelet transfusions. These conditions did not allow physicians to start any invasive approaches. After 14 days, ARDS worsened whereas bone marrow recovered, making possible the beginning of an invasive mechanical ventilation, with low positive end-expiratory pressure and a low tidal volume. Moreover, an immediate extracorporeal CO2 removal (ECCO2R) therapy was added. Despite these efforts, no improvement was achieved, and that is why venovenous ECMO throughout femoral-jugular cannulation was applied. A full protective lung ventilation by ultralow tidal volumes was guaranteed. After 2 weeks of ECMO, a gradual weaning from ECMO support was started and completed after two days. No ECMO-related complications were registered. In the end, the patient started her weaning from the mechanical ventilation and reached 12 hours of spontaneous ventilation in oxygen therapy. Discussion. ECMO is used as a rescue therapy in patients affected by severe respiratory failure with life-threatening hypoxia and respiratory acidosis nonresponsive to other maneuvers. However, immunosuppression and coagulopathies of hematological malignancies are considered relative contraindications for ECMO, while long-lasting respiratory failure represents another relative contraindication to extracorporeal support. ECMO could be a valid option to improve the survival of hematological patients with severe ARDS and thrombocytopenia, and management could change case by case, even if high incidence of recurrency.

Conventional extracorporeal CO2 removal systems require blood flow rates of 1 to 2.5 L/min in the extracorporeal circuit. We hypothesized that standard hemofiltration equipment can be combined with a high-performance extracorporeal lung to achieve high rates of CO2 removal at lower blood flow rates. To test this hypothesis, we performed experiments on nine sheep to examine the extent to which CO2 elimination can be achieved at blood flow rates less than 600 mL/min using a 5-m2 hollow fiber membrane lung with countercurrent gas flow, combined with a hemofiltration blood pump, and connected to femoral arterial and venous hemodialysis catheters. CO2 eliminations of 130 to 180 mL/min at standard temperature and pressure were achieved with blood flow rates in the range 470 to 600 mL/min. With a pumpless artery-to-vein shunt, up to 90 mL/min of CO2 at standard temperature and pressure was eliminated. However, in this mode, the resistance of the access catheters and tubing was the main factor limiting CO2 elimination. Standard hemofiltration equipment may be combined with a hollow fiber membrane lung to remove the equivalent of a high proportion of the basal metabolic CO2 production of an adult human at low blood flow rates. Use of this technology would bring extracorporeal CO2 removal within the budget and capability of more ICUs.

Lesch-Nyhan disease (LND) is an X-linked disorder of purine metabolism, associated with self-mutilation, dystonia, and chorea. Seizures are uncommon in LND. Patients with LND are at risk for sudden and unexpected death. The etiology of this is unknown, but appears to occur from a respiratory process. We propose that respiratory failure secondary to subclinical seizure may lead to sudden death in these patients. We report a case of an 11-year-old boy with LND who had two episodes of nocturnal gasping. The second event was immediately followed by a 10min generalized seizure. Upon arrival at the hospital, an arterial blood gas test revealed a severe respiratory acidosis. Following aggressive treatment of his seizures, this patient did well, and was discharged home on oxcarbazepine with rectal diazepam. No further seizures have been noted in 1 year of follow-up. In this case report and review, we hypothesize that sudden death from respiratory failure in Lesch-Nyhan disease may in some cases be due to seizure-induced respiratory failure, akin to sudden unexpected death in epilepsy (SUDEP). We suggest screening for paroxysmal respiratory events; consideration of electroencephalography for patients with LND presenting in respiratory distress or failure; and consideration of more aggressive treatment of seizures in these patients. Brief Summary:We present an 11-year-old boy with Lesch-Nyhan disease (LND) who developed respiratory failure and severe respiratory acidosis from his first known seizure, which evolved to subclinical status epilepticus. We propose that patients with LND have a predisposition to respiratory failure and sudden death, which in some cases may be provoked by seizure (sudden unexpected death in epilepsy, or SUDEP).

The long-term outcome of infants with severe respiratory distress syndrome can be improved by optimizing surfactant therapy and minimizing the risk for pulmonary barovolutrauma and oxygen toxicity. The authors hypothesized that this may be achieved with low frequency ventilation and extracorporeal CO2 removal (LFV-ECCO2R), in combination with intratracheal instillation of a large fluid volume with diluted surfactant. Lung lavaged rabbits were initially ventilated with continuous positive pressure ventilation. The rabbits were randomized to treatment with LFV-ECCO2R and surfactant (experimental group), or surfactant only (control group). In the experimental group, the rabbits were treated with a large volume (16 ml/kg) of diluted surfactant (6.25 mg/ml) at a dose of 100 mg/kg body weight. After surfactant therapy, the FiO2 100% was gradually decreased. During 4 hours, the extracorporeal bloodflow was adjusted to maintain the PaCO2 between 4.0-6.0 kPa. Thereafter, the rabbits were allowed to breathe spontaneously with 2.5 cm H2O continuous positive airway pressure ventilation (CPAP) and 40% oxygen. In the control group, the rabbits received the same surfactant therapy. During the study period, the rabbits remained ventilated with an inspiratory oxygen concentration (FiO2) of 100% for 4 hours. The ventilator flow was adjusted to maintain the PaCO2 between 4.0 and 6.0 kPa. Thereafter, positive-end expiratory pressure was decreased to 2.5 cm H2O and FiO2 was gradually decreased to 40%. In the experimental group, FiO2 was decreased to 40% in a stepwise fashion whereby the PaO2 could be maintained easily within the normal range. Extracorporeal flow rates during perfusion ranged from 20-35 ml/kg/min and were sufficient to keep the PaCO2 and pH within normal limits. After 4 hours, the rabbits could breathe spontaneously with CPAP and 40% oxygen, while normal blood gas values were maintained. All rabbits survived the experiment. In the control group, all rabbits experienced severe hypoxemia, despite FiO2 of 100% oxygen and, during the course of weaning, all rabbits died because of hypoxia. In conclusion, the present study demonstrated that barovolutrauma due to mechanical ventilation, and oxygen toxicity due to high FiO2, can be minimized in an animal model of acute respiratory failure by the combination of LFV-ECCO2R and surfactant therapy.

I have read with great interest the article by Dr. Hermon et al, who reported that surfactant application in children with severe respiratory failure treated with ECMO was associated with improved lung volume and pulmonary mechanics [1]. Although these findings need to be confirmed in prospective studies these results are very promising. Based on a series of animal studies we advocated already more than 10 years ago to use a combination of surfactant therapy and extracorporeal life support for the treatment of severe respiratory failure. We observed that one possibility is the combination with intratracheal instillation of a large fluid volume with diluted surfactant and low frequency ventilation and extracorporeal CO2 removal (LFV-ECCO2R).

Lung-protective mechanical ventilation with low tidal volumes (V(T)) is often associated with hypercapnia (HC), which may be unacceptable in patients with brain injury. CO2 removal using a percutaneous extracorporeal lung assist (pECLA) enables normocapnia despite low V(T), but its effects on regional cerebral blood flow (rCBF) remain ambiguous. We hypothesized that reversal of HC by pECLA impairs rCBF in a porcine lung injury model. Lung injury was induced in 9 anesthetized pigs by hydrochloric acid aspiration. rCBF and systemic hemodynamics were measured by colored microsphere technique and transpulmonary-thermodilution during a randomized sequence of 4 experimental situations: pECLA shunt-on (1) with HC and (2) without HC, pECLA shunt-off (3) with HC and (4) without HC. HC increased rCBF (P<0.05). CO2 removal with pECLA resulting in normocapnia, decreased rCBF to levels comparable to those without pECLA and normocapnia. HC resulted in increased cardiac output (+25.5%). Cardiac output was highest during HC with pECLA shunt (+44.9%). During pECLA with CO2 removal, cardiac output (+38.1%) decreased compared with pECLA without CO2 removal, but stayed higher than during normocapnia/no pECLA shunt (P<0.05). In this animal model, mechanical ventilation with low V(T) was associated with HC and increased rCBF. CO2 removal by pECLA restored normocapnia, reduced rCBF to levels of normocapnia, but required a higher systemic blood flow for the perfusion of the pECLA device. If these results could be transferred to patients, extracorporeal CO2 removal might be an option for treatment of combined lung and brain injury in condition of a sufficient cardiac flow reserve.

Noninvasive Positive Pressure Ventilation Via Face Mask: First-Line Intervention in Patients With Acute Hypercapnic and Hypoxemic Respiratory Failure

To assess the response to initial oxygenation strategy according to clinical variables available at admission. Multicenter cohort study. Thirty French and Belgium medical ICU. Immunocompromised patients with hypoxemic acute respiratory failure. None. Data were extracted from the Groupe de Recherche en Reanimation Respiratoire du patient d'Onco-Hématologie database. Need for invasive mechanical ventilation was the primary endpoint. Secondary endpoint was day-28 mortality. Six-hundred forty-nine patients were included. First oxygenation strategies included standard oxygen (n = 245, 38%), noninvasive ventilation (n = 285; 44%), high-flow nasal cannula oxygen (n = 55; 8%), and noninvasive ventilation + high-flow nasal cannula oxygen (n = 64; 10%). Bilateral alveolar pattern (odds ratio = 1.67 [1.03-2.69]; p = 0.04), bacterial (odds ratio = 1.98 [1.07-3.65]; p = 0.03) or opportunistic infection (odds ratio = 4.75 [2.23-10.1]; p < 0.001), noninvasive ventilation use (odds ratio = 2.85 [1.73-4.70]; p < 0.001), Sequential Organ Failure Assessment score (odds ratio = 1.19 [1.10-1.28]; p < 0.001), and ratio of PaO2 and FIO2 less than 100 at ICU admission (odds ratio = 1.96 [1.27-3.02]; p = 0.0002) were independently associated with intubation rate. Day-28 mortality was independently associated with bacterial (odds ratio = 2.34 [1.10-4.97]; p = 0.03) or opportunistic infection (odds ratio = 4.96 [2.11-11.6]; p < 0.001), noninvasive ventilation use (odds ratio = 2.35 [1.35-4.09]; p = 0.003), Sequential Organ Failure Assessment score (odds ratio = 1.19 [1.10-1.28]; p < 0.001), and ratio of PaO2 and FIO2 less than 100 at ICU admission (odds ratio = 1.97 [1.26-3.09]; p = 0.003). High-flow nasal cannula oxygen use was neither associated with intubation nor mortality rates. Some clinical characteristics at ICU admission including etiology and severity of acute respiratory failure enable to identify patients at high risk for intubation.

Acute hypercapnic respiratory failure is a rare but life-threatening complication in grossly obese patients with severe obstructive sleep apnoea (OSA). Facial trauma or upper airway surgery, respiratory tract infections, bronchospasm, use of pain medication and concomitant obstructive or restrictive pulmonary impairment predispose to the development of respiratory failure in such patients. We present a case of a morbidly obese male patient in whom moderately severe OSA (the apnoea-hypoponea index, AHI of 37/hour) was treated with uvulapalatopharyngoplasty (UPPP) because he declined treatment with non-invasive ventilation. The early postoperative period was complicated by severe hypercapnic respiratory failure in association with worsening of OSA: arterial PO2 was 4.14 kPa, PCO2 9.7 kPa, AHI increased to 93.8/hour, minimal nocturnal arterial oxygen saturation was 46%. Therapy with non-invasive ventilation using bi-level positive airway pressure (BiPAP) was initiated immediately, and resulted in marked improvements in the patient's clinical condition, in association with the improvements in arterial blood gases. Before the discharge, nocturnal continuous positive airway pressure (CPAP) therapy to treat OSA on the long-term basis was initiated. Two months after the release, the patient's blood gases were within the normal range, and he reported marked improvements in his clinical condition including alleviation of daytime sleepiness and increased physical endurance. Our case demonstrates that in the presence of severe OSA, life-threatening hypoxaemia and hypercapnia were successfully alleviated using BiPAP in the postoperative period after UPPP.

<b>Background:</b> While few international studies have assessed the association between omeprazole use and the risk of <i>Clostridium difficile</i> infection (CDI), research into this is lacking in Saudi Arabia and the Middle East region. The aim of this study was to determine whether exposure to omeprazole is associated with the risk of <i>Clostridium difficile</i> infection in a sample of hospitalized Saudi patients. <b>Methodology:</b> A retrospective matched case-control study was conducted at the King Abdulaziz Medical City in Riyadh, Saudi Arabia, from 1 August 2010 through 31 July 2015. The analysis included a total of 200 patients: 100 CDI cases and 100 matched controls. <b>Results:</b> The majority (60%, 120 out of 200) of patients had received proton pump inhibitors (PPIs), and a minority (18.5%, 37 out of 200) had received omeprazole. The PPI use was insignificantly higher in CDI cases than in controls. However, the use of omeprazole was significantly higher in CDI cases compared with controls. Specifically, patients receiving omeprazole were two times more likely to develop CDI compared with controls (aOR = 2.1, 95% confidence interval (CI) = (1.007-4.437)). After adjusting for potential predictors of CDI, watery diarrhea (aOR = 59.1, 95% CI = 19.831-175.974) and abdominal pain (aOR = 7.5, 95% CI = 2.184-25.445) were found to be independent predictors of CDI. <b>Conclusions:</b> The data suggests that PPIs were commonly used in patients admitted to King Abdulaziz Medical City in Riyadh: six out of ten patients received PPIs. The findings support a possible association between the use of omeprazole and a high risk of CDI. To confirm causality, the link between omeprazole and CDI should be assessed in a large interventional study.

High-frequency oscillatory ventilation (HFOV) remains an option for the management of critically ill children when conventional mechanical ventilation fails. However, its use is not widespread, and there is wide variability reported with respect to how it is used. To describe the frequency, indications, settings and outcomes of HFOV use among paediatric patients with a primary respiratory disorder admitted to a tertiary paediatric intensive care unit (PICU). The study was a 2-year, single-centre, retrospective chart review. Thirty-four (32.7%) patients were managed with HFOV in the PICU during the study period. Thirty-three of the 34 patients had paediatric acute respiratory distress syndrome. Indications for HFOV were inadequate oxygenation in 17 patients (50%), and refractory respiratory acidosis in 15 patients (44.1%) (2 patients did not fit into either category). Approaches to the setting of HFOV varied considerably, particularly with respect to initial pressure around the airways. HFOV was effective at improving both oxygenation, with a median (interquartile range (IQR)) decrease in oxygenation index of 6.34 (5.0 - 9.5), and ventilation with a the median decrease in PaCO2 of 67.6 (46.2 - 105.7) mmHg after 24 hours. Overall mortality was 29.4% in the HFOV group, which is consistent with other studies. HFOV remains an effective rescue ventilatory strategy, which resulted in rapid and sustained improvement in gas exchange in patients with severe hypoxaemia and/or severe respiratory acidosis, particularly in the absence of extracorporeal support. However, the variability in practice and the adverse effects described highlight the need for future high-quality randomised controlled trials to allow for development of meaningful guidelines to optimise HFOV use. This study describes the use and outcomes of high-frequency oscillatory ventilation (HFOV) in a South African paediatric intensive care unit, thus addressing a local knowledge gap and providing evidence of the continued efficacy of HFOV for severe hypoxaemia and refractory respiratory acidosis in settings without access to extracorporeal technologies.